The chief purpose of this research plan is to expand R01DA13806, an investigation of antiretroviral therapy (ART) and liver disease among persons dually-infected with HIV and hepatitis C virus (HCV). In the first four years of research, we provided the first unbiased estimate of the burden of liver disease in this setting by performing liver biopsies on randomly-selected, HIV/HCV coinfected members of the Johns Hopkins HIV Clinic Cohort. The magnitude of liver fibrosis varied substantially from person to person, and we have reported unexpected progression of fibrosis in our ongoing prospective evaluation. Consequently, in the next five years our first aim is to continue to characterize the rate of progression of liver fibrosis in an expanded group of 250 HIV/HCV coinfected persons, identifying disease cofactors and testing the hypothesis that the risk of progression is lower in persons taking ART. Building on the resources established through our prospective study of 250 persons, our second specific aim is to identify noninvasive markers of liver fibrosis in HIV/HCV coinfected persons in collaboration with Dr. Afdhal at Harvard. During the first cycle of this grant, initially-unforeseen, long-term metabolic complications of ART were described by other investigators. Accordingly, we already have expanded our research to provide the first evaluation of the burden of hepatic steatosis among HIV/HCV coinfected persons. In the next cycle, our third aim is to assess the natural history of liver steatosis among HIV/HCV coinfected persons. The central theme of this research program remains evaluation of ART and the liver in HIV/HCV coinfected persons. Our aims have expanded to answer the most pressing research questions as detailed in the 2004 NIH Action Plan for Liver Disease Research. Key collaborations were established with internationally recognized experts on fibrosis markers (Dr. Afdhal) and metabolic complications of ART (Dr. Powderly) to supplement the strong research environment at Johns Hopkins that has already produced some of the most significant studies on liver disease in this setting.